A fundamental, long-term objective of this project is to develop an integrative, multidisciplinary research model that evaluates the mechanisms underlying environmental control of seasonal variation in brain and behavior relationships. Traditionally, the hypothalamic gonadotropin-releasing hormone (GnRH) system has been considered to be the pinnacle of hierarchical control of reproductive function. However, the upstream mechanisms governing how the GnRH neuronal system receives, integrates, and responds to environmental cues remain largely unknown. The specific research objectives are to test the hypothesis that long-term timekeeping mechanisms in calendar cells both generate endogenous circannual rhythms in GnRH secretion and integrate these rhythms with environmental and social cues. The experiments described herein aim to test this hypothesis by investigating the neuroanatomical and neuroendocrinological relationships between GnRH neurons, the neuropeptide kisspeptin, and the pineal hormone melatonin. The anatomical relationships between these neural and hormonal signals will be evaluated using a combination of double-label immunohistochemistry and in situ hybridization to identify co-expression patterns of clock genes, melatonin receptors, GnRH, kisspeptin, and kisspeptin receptors. Functional tests of this neuroanatomical circuit in the control of reproduction will then be performed using a series of pharmacological manipulations and behavioral experiments. Collectively, these experiments will provide valuable insight into how extrinsic environmental and social cues are integrated with intrinsic neural, physiological, and behavioral responses, a process that is crucial to the survival and fitness of all species. Studies of the molecular mechanisms underlying this integration are imperative for understanding the factors that regulate and control plasticity in the nervous system. Such fundamental knowledge about the nature of neuroplasticity will provide a more thorough understanding of mental health disorders and may aid in the development of potential avenues for reducing the burdens of illness and disability. The relevance of this research to public health is evident in the profound role of brain plasticity in the neuroscience of mental health. For example, disruptions in circadian biology and melatonin signaling have been implicated in age-related changes in brain function as well as mental disease states such as seasonal affective disorder, depression, bipolar disorder, and Alzheimer's disease. The results obtained from this research will provide a foundation for developing an integrative model for the complex mechanisms that mediate seasonal and persistent changes in brain and behavior relationships.